Aurora-A overexpression and aneuploidy predict poor outcome in serous ovarian carcinoma Heini Lassus a , Synnöve Staff b , Arto Leminen a , Jorma Isola b , Ralf Butzow a,c, ⁎ a Department of Obstetrics and Gynecology, Helsinki University Central Hospital, Hospital District of Helsinki and Uusimaa, Research Laboratory, Biomedicum Helsinki, P.O. Box 700 (Haartmanink. 8), FIN-00029 HUS, Finland b Institute of Medical Technology, University and University Hospital of Tampere, Biokatu 6, 33520 Tampere, Finland c Department of Pathology, Helsinki University Central Hospital, P.O. Box 21 FIN-00014 University of Helsinki, Finland abstract article info Article history: Received 9 July 2010 Keywords: Aurora-A Ovarian cancer Serous histology Ploidy Prognosis Objective. Aurora-A is a potential oncogene and therapeutic target in ovarian carcinoma. It is involved in mitotic events and overexpression leads to centrosome amplification and chromosomal instability. The objective of this study was to evaluate the clinical significance of Aurora-A and DNA ploidy in serous ovarian carcinoma. Methods. Serous ovarian carcinomas were analysed for Aurora-A protein by immunohistochemistry (n = 592), Aurora-A copy number by CISH (n = 169), Aurora-A mRNA by real-time PCR (n = 158) and DNA ploidy by flowcytometry (n = 440). Results. Overexpression of Aurora-A was found in 27% of the tumors, cytoplasmic overexpression in 11% and nuclear in 17%. The cytoplasmic and nuclear overexpression were nearly mutually exclusive. Both cytoplasmic and nuclear overexpression were associated with shorter survival, high grade, high proliferation index and aberrant p53. Interestingly, only cytoplasmic expression was associated with aneuploidy and expression of phosphorylated Aurora-A. DNA ploidy was associated with poor patient outcome as well as aggressive clinicopathological parameters. In multivariate analysis, Aurora-A overexpression appeared as an independent prognostic factor for disease-free survival, together with grade, stage and ploidy. Conclusions. Aurora-A protein expression is strongly linked with poor patient outcome and aggressive disease characteristics, which makes Aurora-A a promising biomarker and a potential therapeutic target in ovarian carcinoma. Cytoplasmic and nuclear Aurora-A protein may have different functions. DNA aneuploidy is a strong predictor of poor prognosis in serous ovarian carcinoma. © 2010 Elsevier Inc. All rights reserved. Introduction Aurora kinases are a family of serine/threonine kinases consisting of three members (A, B and C) that are involved in mitotic events. Aurora A (STK15/BTAK) is known to be involved with centrosome function, mitotic entry and spindle assembly [1]. Aurora A was first identified as the product of gene BTAK on chromosome 20q13, a region which is amplified in various cancers [2,3]. Overexpression of Aurora-A leads to centrosome amplification and chromosomal instability [3], which results in apoptosis in the presence of intact p53 [4]. Mice with intact p53 that overexpress Aurora-A develop only small hyperplastic changes of the mammary gland, whereas over- expression of Aurora-A in p53-deficient mice results in development of precancerous lesions histologically similar to atypical ductal hyperplasia [5,6]. In addition to direct involvement in chromosomal segregation, Aurora-A overexpression enhances cell migration and induces chemoresistance, by activating Akt pathway [7,8]. Because of the putative oncogenic role of Aurora kinases, there has been interest in developing small molecular inhibitors against them [9]. Most of the currently available molecules target more than one Aurora kinase, but some are Aurora-A specific. In an orthotopic mouse model of ovarian cancer, pan-Aurora kinase inbitor MK-0457 reduced tumor cell proliferation and increased apoptosis [10]. The clinical correlations of Aurora-A expression in ovarian cancer have been inconsistent: some have claimed association with poor prognosis [11,12], whereas others have found no correlation, or even positive prognostic effect [13,14]. It is known that molecularly targeted drugs affect only tumors where the particular gene has a pathogenetic role (e.g. ERBB2 amplification in mammary carcinoma), but no predictive biomarker is available to select patients for treatment with an Aurora kinase inhibitor. Ovarian carcinoma consists of several histological types, which were previously considered as one entity. However, it has been shown that the histological types have distinct molecular pathogen- esis and clinical behavior [15–19]. Therefore we have concentrated on Gynecologic Oncology 120 (2011) 11–17 ⁎ Corresponding author. Department of Pathology, Helsinki University Central Hospital, P.O. Box 21 FIN-00014 University of Helsinki, Finland. E-mail address: ralf.butzow@hus.fi (R. Butzow). 0090-8258/$ – see front matter © 2010 Elsevier Inc. All rights reserved. doi:10.1016/j.ygyno.2010.09.003 Contents lists available at ScienceDirect Gynecologic Oncology journal homepage: www.elsevier.com/locate/ygyno